Process for making 2-aryl-3-aryl-5-halo pyridines useful as COX-2 inhibitors

ABSTRACT

The invention encompasses a process for making compounds of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases. ##STR1##

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of U.S. application No.09/060,731 filed on Apr. 15, 1998, copending herewith, which was basedupon a provisional application, Ser. No. 60/045,642, filed on Apr. 18,1997, now lapsed, priority of which is claimed hereunder.

BACKGROUND OF THE INVENTION

This invention concerns a process for making certain anti-inflammatorycompounds. In particular, the application concerns a process for makingcompounds of formula I as disclosed hereunder, which compounds arepotent cyclooxygenase-2 inhibitors.

Non-steroidal, antiinflammatory drugs exert most of theirantiinflammatory, analgesic and antipyretic activity and inhibithormone-induced uterine contractions and certain types of cancer growththrough inhibition of prostaglandin G/H synthase, also known ascyclooxygenase. Up until recently, only one form of cyclooxygenase hadbeen characterized, this corresponding to cyclooxygenase-1 or theconstitutive enzyme, as originally identified in bovine seminalvesicles. Recently the gene for a second inducible form ofcyclooxygenase (cyclooxygenase-2) has been cloned, sequenced andcharacterized from chicken, murine and human sources. This enzyme isdistinct from the cyclooxygenase-1 which has now also been cloned,sequenced and characterized from sheep, murine and human sources. Thesecond form of cyclooxygenase, cyclooxygenase-2, is rapidly and readilyinducible by a number of agents including mitogens, endotoxin, hormones,cytokines and growth factors. As prostaglandins have both physiologicaland pathological roles, we have concluded that the constitutive enzyme,cyclooxygenase-1, is responsible, in large part, for endogenous basalrelease of prostaglandins and hence is important in their physiologicalfunctions such as the maintenance of gastrointestinal integrity andrenal blood flow. In contrast, we have concluded that the inducibleform, cyclooxygenase-2, is mainly responsible for the pathologicaleffects of prostaglandins where rapid induction of the enzyme wouldoccur in response to such agents as inflammatory agents, hormnones,growth factors, and cytokines. Thus, a selective inhibitor ofcyclooxygenase-2 will have similar antiinflammatory, antipyretic andanalgesic properties to a conventional non-steroidal antiinflammatorydrug, and in addition would inhibit hormone-induced uterine contractionsand have potential anti-cancer effects, but will have a diminishedability to induce some of the mechanism-based side effects. Inparticular, such a compound should have a reduced potential forgastrointestinal toxicity, a reduced potential for renal side effects, areduced effect on bleeding times and possibly a lessened ability toinduce asthma attacks in aspirin-sensitive asthmatic subjects.

WO 96/24585 published Aug. 15, 1996 and WO 96/10012, published Apr. 4,1996 disclose methods of making 2-aryl-3-aryl-pyridines. In theinvention disclosed herein, 2-aryl-3-aryl-pyridines are prepared in asimple to conduct, 1 step condensation from readily available startingmaterials. It is, therefore, surprisingly convenient and more efficientthan the previously described procedure, in which the 2-aryl-3-arylpyridine was constructed by serial stepwise addition of the aryl groupsto the central pyridine ring. Moreover, the process of the instantinvention is surprisingly superior in that expensive palladium reagentsare not required, and the cumbersome protection/de-protection sequenceof the prior art process is avoided.

The preparation of 2-chloromalondialdehyde was first accomplished byDiekmann in 1904 (W. Dieckmann, L. Platz, Ber. Deut. Chem. Ges. 1904,37, 4638). The chemistry of 2-halomalondialdehydes was thoroughlyreviewed in 1975 (C. Reichardt and K. Halbritter, Angew. Chem. Int. Ed.1975, 14, 86). This review does not mention a pyridine synthesis usingthese reagents. The only recorded use of 2-chloromalondialdehyde for thepreparation of a pyridine is in a recent patent application (F. J.Urban, U.S. Pat. No. 5,206,367 to Pfizer and Brackeen, M. and Howard, H.R. European Patent Application number 89307339.5 (EP 0 352 959) toPfizer), where chloromalondialdehyde is first converted to2,3-dichloroacrolein, which is subsequently condensed with the enaminederived from 1,3-cyclohexanedione to give the annulated pyridine in 28%yield.

A recent comprehensive review of pyridine synthesis and reactivity (D.Spitzner in Methoden der Organischen Chemie (Houben-Weyl), pages 286 to686, Vol. E 7b, Editor R. P. Kreher, 1992, Georg Thieme Verlag) gives noexamples for the use of halomalondialdehydes for the pyridine synthesis.Nitromalondialdehyde has been condensed with ethyl-2-amino-crotonate togive the 5-nitropyridine, albeit in lower yield (35-50%) (J. M. Hoffmanet.al. J. Org. Chem. 1984, 49, 193 and P. E. Fanta, J. Am. Chem. Soc.1953, 75, 737). The use of ethoxycarbonyl malondialdehyde derivativesleads to 5-ethoxycarbonyl pyridines (S. Torii et. al. Synthesis, 1986,400).

SUMMARY OF THE INVENTION

The invention encompasses a process for making compounds of Formula Iuseful in the treatment of inflammation and other cyclooxygenase-2mediated diseases ##STR2##

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect the invention encompasses a process for makingcompounds of Formula I useful in the treatment of inflammation and othercyclooxygenase-2 mediated diseases ##STR3## wherein: R¹ is selected fromthe group consisting of:

(a) CH₃,

(b) NH₂,

(c) NHC(O)CF₃ and

(d) NHCH₃ ;

Ar is a mono-, di-, or trisubstituted phenyl or pyridinyl (or theN-oxide thereof), wherein the substituents are selected from the groupconsisting of:

(a) hydrogen,

(b) halo,

(c) C₁₋₄ alkoxy,

(d) C₁₋₄ alkylthio,

(e) CN,

(f) C₁₋₄ alkyl and

(g) C₁₋₄ fluoroalkyl;

R² is selected from the group consisting of:

(a) F, Cl, Br or I,

(b) CN and

(c) azide,

the process comprising:

condensing a compound of formula A1 ##STR4## under acidic conditions,and optionally in the presence of a non-reactive solvent and in thepresence of an ammonium reagent, with compound A2 ##STR5## to yield acompound of Formula I.

As will be appreciated by those of skill in the art, in the general casethe reagents themselves provide the acidic condition. Therefore, the useof a non-reagent acid is not necessary. However, the addition of anacid, such as acetic or propionic or another carboxylic acid is withinthe scope of the invention.

For purposes of this specification non-reactive solvent includestetrahydrofuran, dioxane, C₁₋₆ alkanol, and toluene.

For purposes of this specification, the ammonium reagent is intended toinclude ammonia and ammonium salts such as ammonium acetate and ammoniumpropionate. Moreover a mixture ammonia reagent species is included inthe term ammonia reagent.

The molar ratio of compound A1 to A2 can typically be varied from 2:1 to1:2; preferably 1:1 to 1.5. Excess compound A1 is typically used. Themolar ratio of compound Al to ammonium reagent can typically be variedfrom 1:1 to 1:10. The reaction step may conveniently be conducted at atemperature range of 40 to 180° C.; preferably 80 to 140° C. and isallowed to proceed until substantially complete in from 2 to 18 hours;typically 6 to 12 hours.

In a second aspect the invention encompasses a process for makingcompounds of Formula I useful in the treatment of inflammation and othercyclooxygenase-2 mediated diseases ##STR6## wherein: R¹ is selected fromthe group consisting of:

(a) CH₃,

(b) NH₂,

(c) NHC(O)CF₃ and

(d) NHCH₃ ;

Ar is a mono-, di-, or trisubstituted phenyl or pyridinyl (or theN-oxide thereof), wherein the substituents are chosen from the groupconsisting of:

(a) hydrogen,

(b) halo,

(c) C₁₋₄ alkoxy,

(d) C₁₋₄ alkylthio,

(e) CN,

(f) C₁₋₄ alkyl and

(g) C₁₋₄ fluoroalkyl;

R² is selected from the group consisting of:

(a) F, Cl, Br or I,

(b) CN and

(c) azide,

the process comprising:

(a) reacting a compound of formula A2: ##STR7## in the presence of asecond non-reactive solvent with a strong base to yield the enolate offormula B1: ##STR8## wherein M is potassium, lithium or sodium.

For purposes of this specification, the strong base shall includelithium, potassium or sodium diisopropylamide, lithium, potassium orsodium bis(trimethylsilyl)amide, lithium, potassium or sodium hydride,and lithium, potassium or sodium amide.

For purposes of this specification the second non-reactive solventincludes tetrahydrofuran, dioxane, toleune and ethers.

The molar ratio of compound A2 to base can typically be varied from 1:1to 1:1.5. Excess base is typically used. The reaction step mayconveniently be conducted at a temperature range of -80 to 40° C.;preferably -10 to 20° C. and is allowed to proceed until substantiallycomplete in from 1 to 3 hours; typically 1 to 2 hours.

(b) reacting a compound of formula B1 ##STR9## in the presence of athird non-reactive solvent with compound B2 ##STR10## wherein R³ is aleaving group such as tosyl, mesyl or halo. which after heating in thepresence of ammonia reagent, yields a compound of formula I.

For purposes of this reaction, the third non-reactive solvent shallinclude tetrahydrofuran, toluene and dioxane. The molar ratio ofcompound B1 to 2.3-dichloroacrolein can typically be varied from 1:1.5to 1.5:1; preferably 1:1 to 1.5. Excess 2.3-dichloroacrolein istypically used. The reaction step may conveniently be conducted at atemperature range of 0 to 80° C.; preferably 20 to 50° C. and is allowedto proceed until substantially complete in from 2 to 18 hours; typically4 to 12 hours.

With regard to the both aspects of the invention, R² is preferablyhalogen, most preferably F or Cl, most preferably Cl. It is preferablethat R3 be the same as R².

With regard to both aspects of the invention a preferred sub-genus offormula I is that wherein Ar is a mono-, or disubstituted pyridinyl.Within this sub-genus, the 3-pyridinyl isomers are particularlypreferred.

Again with regard to both aspects of the invention another preferredsub-genus of formula I is that wherein R¹ is CH₃ or NH₂. Generally, CH₃is preferred for COX-2 specificity and NH₂ is preferred for potency.

Again with regard to both aspects of the invention another preferredsub-genus of formula I is that wherein the Ar is unsubstituted orsubstituted with CH₃.

The Compound of Formula I is useful for the relief of pain, fever andinflammation of a variety of conditions including rheumatic fever,symptoms associated with influenza or other viral infections, commoncold, low back and neck pain, dysmenorrhea, headache, toothache, sprainsand strains, myositis, neuralgia, synovitis, arthritis, includingrheumatoid arthritis degenerative joint diseases (osteoarthritis), goutand ankylosing spondylitis, bursitis, burns, injuries, followingsurgical and dental procedures. In addition, such a compound may inhibitcellular neoplastic transformations and metastic tumor growth and hencecan be used in the treatment of cancer. Compounds of formula I may alsobe useful for the treatment of dementia including pre-senile and seniledementia, and in particular, dementia associated with Alzheimer Disease(ie Alzheimer's dementia).

By virtue of its high cyclooxygenase-2 (COX-2) activity and/or itsselectivity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1) asdefined above, compounds of formula I will prove useful as analternative to conventional non-steroidal antiinflammatory drugs(NSAID'S) particularly where such non-steroidal antiinflammatory drugsmay be contra-indicated such as in patients with peptic ulcers,gastritis, regional enteritis, ulcerative colitis, diverticulitis orwith a recurrent history of gastrointestinal lesions; GI bleeding,coagulation disorders including anemia such as hypoprothrombinemia,haemophilia or other bleeding problems (including those relating toreduced or impaired platelet function); kidney disease (eg impairedrenal function); those prior to surgery or taking anticoagulants; andthose susceptable to NSAID induced asthma.

Compounds of the present invention are inhibitors of cyclooxygenase-2and are thereby useful in the treatment of cyclooxygenase-2 mediateddiseases as enumerated above. This activity is illustrated by theirability to selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.Accordingly, in one assay, the ability of the compounds of thisinvention to treat cyclooxygenase mediated diseases can be demonstratedby measuring the amount of prostaglandin E₂ (PGE₂) synthesized in thepresence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2 and acompound of formula I. The IC50 values represent the concentration ofinhibitor required to return PGE₂ synthesis to 50% of that obtained ascompared to the uninhibited control. Illustrating this aspect, we havefound that the Compounds of the Examples are more than 100 times moreeffective in inhibiting COX-2 than they are at inhibiting COX-1. Inaddition they all have a COX-2 IC50 of 1 nM to 1 mM. By way ofcomparison, Ibuprofen has an IC50 for COX-2 of 1 mM, and Indomethacinhas an IC50 for COX-2 of approximately 100 nM.

For the treatment of any of these cyclooxygenase mediated diseases,compounds of formula I may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattlesheep, dogs, cats, etc., the compound of the invention is effective inthe treatment of humans.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) all operations were carried out at room or ambient temperature, thatis, at a temperature in the range 18-25° C.; evaporation of solvent wascarried out using a rotary evaporator under reduced pressure (600-4000pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60° C.; thecourse of reactions was followed by thin layer chromatography (TLC) orHigh Pressure Liquid Chromatography (HPLC) and reaction times are givenfor illustration only; melting points are uncorrected and `d` indicatesdecomposition; the melting points given are those obtained for thematerials prepared as described; polymorphism may result in isolation ofmaterials with different melting points in some preparations; thestructure and purity of all final products were assured by at least oneof the following techniques: TLC, mass spectrometry, nuclear magneticresonance (NMR) spectrometry or microanalytical data; yields are givenfor illustration only; when given, NMR data is in the form of delta (d)values for major diagnostic protons, given in parts per million (ppm)relative to tetramethylsilane (TMS) as internal standard, determined at300 MHz or 400 MHz using the indicated solvent; conventionalabbreviations used for signal shape are: s. singlet; d. doublet; t.triplet; m. multiplet; br. broad; etc.: in addition "Ar" signifies anaromatic signal; chemical symbols have their usual meanings; thefollowing abbreviations have also been used v (volume), w (weight), b.p.(boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g(gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq(equivalent(s)).

The following abbreviations have the indicated meanings:

Alkyl Group Abbreviations

Me=methyl

Et=ethyl

n-Pr=normal propyl

i-Pr=isopropyl

n-Bu=normal butyl

i-Bu=isobutyl

s-Bu=secondary butyl

t-Bu=tertiary butyl

c-Pr=cyclopropyl

c-Bu=cyclobutyl

c-Pen=cyclopentyl

c-Hex=cyclohexyl

EXAMPLE 1

    ______________________________________                                        5-Chloro-3(methylsulfonyl)phenyl-2-(3-pyridyl)-pyridine; Compound             ______________________________________                                          #STR11##                                                                     ##STR12##                                                                    ______________________________________                                              2-Chloromalondialdehyde                                                                           4.8 g (0.045 mol)                                     Ketone B 5.0 g (0.018 mol)                                                    Propionic acid 30 mL                                                          Ammonium Acetate 8.4 g (0.11 mol)                                           ______________________________________                                    

A mixture of ketone B (5.0 g), 2-chloromalondialdehyde (4.8 g) andammonium acetate were heated to 130° C. The acetic acid produced wasremoved by distillation and heating continued at 136° C. for 15 hours.The reaction mixture was basified with sodium carbonate, water was addedand the product was extracted into dichloromethane (2×150 mL). Theorganic layers were carbon treated (Dowex), dried (MgSO₄) and thesolvent removed to afford 1 as an off white solid (3.4 g, 55% yield).

    ______________________________________                                         ##STR13##                                                                

    ______________________________________                                              2-Chloromalondialdehyde                                                                           220 mg (2.1 mmol)                                     Oxalyl Chloride 180 mL (2.1 mmol)                                             Toluene 3 mL                                                                  N,N-Dimethylformamide 20 mL                                                 ______________________________________                                    

N,N-dimethyl formamide was added to a slurry of 2-chloromalondialdehyde(220 mg) in toluene. Oxalyl chloride was added and the reaction mixturewas stirred until complete dissolution occurred.

    ______________________________________                                          #STR14##                                                                     ##STR15##                                                                    ______________________________________                                          Ketone B                 500 mg (1.8 mmol)                                    Lithium bis(trimethylsilyl)amide (1 M in THF) 1.8 mL (1.8 mmol)                                         Tetrahydrofuran           15 mL                     2,3-Dichloroacrolein in toluene         2.1 mmol in 3 mL                      toluene                                                                       Ammonium Acetate 1.0 g                                                      ______________________________________                                    

Lithium bis(trimethylsilyl)amide (1.8 mL;1 M in THF) was added dropwiseto ketone B (500 mg) in THF (15 mL) at -78° C. The reaction mixture waswarmed to ambient temperature for 1 hour to form the lithium enolate ofB (see the generic formula B1) before recooling to -78° C. A solution of2,3-dichloroacrolein was added and the temperature allowed to warm toroom temperature. After 1 hour ammonia gas was passed through thesolution and after 30 minutes ammonium acetate (1 g) was added. Thereaction mixture was warmed to 60° C. for 1 hour and poured into aqueoussodium hydroxide (2 M; 100 mL). The product was extracted withdichloromethane (2×150 mL), dried (MgSO4) and the solvent removed toafford 1 (500 mg; 80%).

EXAMPLE 2

    ______________________________________                                          #STR16##                                                                     ##STR17##                                                                    ______________________________________                                          Ketone B                 2.0 g (6.9 mmol)                                     Lithium bis(trimethylsilyl)amide (1 M in THF) 7.5 mL (7.5 mmol)                                         Tetrahydrofuran      30 mL                          2,3-Dichloroacrolein 1.5 g                                                    Ammonium Acetate 4.0 g                                                      ______________________________________                                    

Lithium bis(trimethylsilyl)amide (7.5;1 M in THF) was added dropwise toketone B' (2.0 g) in THF (30 mL) at -50° C. The reaction mixture waswarmed to ambient temperature for 1 hour to form the lithium enolate ofB (see the generic formula B1) before recooling to -50° C. A solution of2,3-dichloroacrolein (1.5g in 2 mL THF) was added and the temperatureallowed to warm to room temperature. After 1 hour ammonia gas was passedthrough the solution and after 30 minutes ammonium acetate (4 g) wasadded. The reaction mixture was warmed to 60° C. for 2 hour and pouredinto aqueous sodium hydroxide (2 M; 200 mL). The product was extractedwith dichloromethane (2×250 mL), dried (MgSO4) and the solvent removedto afford 1' (1.30 g; 53%).

PREPARATION OF STARTING MATERIALS PREP 1 SYNTHESIS OF4-METHYLSULFONYLPHENYLACETIC ACID

    ______________________________________                                          #STR18##                                                                     ##STR19##                                                                    ______________________________________                                          Thioanisole 2 (FW = 124.2, d = 1.058)                                                               50.00 g (0.403 mol, 47.3 mL)                            Ethyloxalyl chloride (FW = 136.5, 82.43 g (0.604 mol, 67.5 mL)                d = 1.222)                                                                    Aluminum chloride (FW = 133.3) 75.13 g (0.564 mol)                            o-dichlorobenzene (ODCB) 112 mL                                             ______________________________________                                    

The ethyloxalyl chloride and ODCB were charged to a flask equipped withan overhead mechanical stirrer and cooled to 0° C. The AlCl₃ was addedslowly. The addition of the AlCl₃ was exothermic. The thioanisole 2 wasadded dropwise via an addition funnel over 1.5 h. The reaction mixturerapidly turns a dark violet color. This addition was also exothermic.

After 1 h, the reaction was complete by HPLC. The reaction was quenchedby the slow addition of 300 mL of 1N HCl at 0° C. After warming to roomtemperature, water and ODCB (50 mL each) were added. The layers weremixed and cut. The organic (bottom) phase was washed with 1×250 mL waterand then dried over MgSO₄.

This quench was also exothermic. The reaction mixture turned from darkviolet to pale green during the quench. The dried ODCB solution wascharged to a Morton flask equipped with mechanical stirring. A solutionof 1N NaOH (800 mL) was added. The biphasic mixture was stirredvigorously and heated to 50° C. Hydrolysis to 3 was complete in 2-3 h byHPLC. The product-containing aqueous phase was taken directly into theWolf-Kishner reaction.

    ______________________________________                                        4-(Methylthio)phenylacetic acid                                               ______________________________________                                         ##STR20##                                                                    ______________________________________                                          3 (in 1N NaOH solution)                                                                             (0.402 mol)                                             Hydrazine (FW = 32.1. 35 wt % in water) 206.14 g (2252 mol, 204 mL)                                  NaOH (5N solution) 5 mL                              ______________________________________                                    

The hydrazine and NaOH were charged to a Morton flask equipped withmechanical stirring. After heating the hydrazine solution to 75° C., thesolution of 3 in NaOH was added over 35-40 min. At the end of theaddition the reaction mixture was brought to reflux for 5 days. HPLCshowed the reaction to be ca. 95% complete at this point. The startingmaterial was largely consumed in under 24 h, but a third peak which tookseveral days to convert to 4. The reaction was acidified withconcentrated HCl to pH=1.5 and extracted with EtOAc (1×750 mL and 1×250mL). The combined product-containing organic phases were washed 2×250 mL1N HCl.

On acidification, the reaction mixture turned bright yellow.

    ______________________________________                                        4-(Methylthio)phenylacetic acid                                               ______________________________________                                          #STR21##                                                                     ##STR22##                                                                    ______________________________________                                          4-(Methylthiophenylacetic acid 4 (FW = 182.3)                                                                  (0.402 mol)                                  Na.sub.2 WO.sub.4.H.sub.2 O (FW = 329.9) 2.64 g (0.008 mol)                   Aliquat 336 (FW =0 404) 8.08 g (0.020 mol)                                    Hydrogen peroxide (FW = 34.0, 30 wt % in 136 g (1.200 mol,                    water)  123 mL)                                                             ______________________________________                                    

A flask equipped for mechanical stirring was charged with 3 (fromreaction above, in EtOAc), Aliquat 336, and Na₂ WO₄ •2H₂ O (dissolved inca. 15 mL H₂ O). Hydrogen peroxide was added slowly via an additionfunnel over ca. 30 min. Completion of reaction was checked by HPLC. Thereaction was washed with 2×400 mL H₂ O and dried over MgSO₄.Quantification of product in the organic layer gave 61.29 g 5 (71% yieldfrom thioanisole). On concentration of the solution, a white solidprecipitated. The slurry was filtered, and washed with hexanes. Recoverywas 49.02 g 5 (57% from thioanisole).

    ______________________________________                                        Ivanov-Claisen Condensation for the Preparation of                              1-(3-pyridyl)-2-(4-methylsulfonylphenyl)-ethane-1-one                       ______________________________________                                            #STR23##                                                                    #STR24##                                                                       -                                                                             ##STR25##                                                                  ______________________________________                                              4-(Methylsulfonylbenzyl-3-pyridylketone from ethyl nicotinate and              4-methylsulfonylphenylacetic acid                                      ______________________________________                                                  4-Methylsulfonylphenyl Acetic Acid                                                                 10 g   (46.7 mmol)                               (MW = 217)                                                                    t-Butyl magnesium chloride (1N/THF) 128.11 ml  (128.11 mmol)                  Ethyl nicotinate (MW = 151.2; d = 1.107) 5.54 ml (39.4 mmol)                  THF 440 ml                                                                  ______________________________________                                    

Phenyl acetic acid was dissolved in THF under nitrogen. 1.9 equivalents(88.73 ml) of t-butyl magnesium chloride were added over 5 minutes tothe solution. The Reaction was exothermic. The temperature rose from 20°C. to 50° C. After addition of the first equivalent of t-butyl magnesiumchloride, the solution turned red.

The reaction temperature was maintained at 50° C. After one hour, 0.5equivalents of ethyl nicotinate were added. The solution turned yellowand a white precipitate formed. After one hour, 0.5 equivalents oft-butyl magnesium chloride were added at 50° C. The solution turned red.This sequence of addition was repeated using 0.25 eq., 0.125 eq., 0.0625eq. of ethyl nicotinate and t-butyl magnesium chloride. The reactionmixture was aged for 1 hour between each addition.

After the last addition, the reaction was quenched by adding thereaction mixture into vigorously stirred 2N hydrochloric acid (100 ml).The solids at the bottom of the reaction mixture dissolved witheffervescence when stirred in hydrochloric acid.

The pH of the aqueous phase of the reaction mixture was adjusted to 10with sodium carbonate. LC assay showed 91% yield of ketone

Preparation of 4-Methylsulfonylbenzaldehyde

The preparation follows the procedure of Ulman JOC, pp4691 (1989).

    ______________________________________                                        4-Methylsulfonylbenzaldehyde (2) from 4-Fluorobenzaldehyde                    ______________________________________                                         ##STR26##                                                                    ______________________________________                                          4-Fluorobenzaldehyde (MW = 124.11; d = 1.157)                                                          23.3 ml (217 mmol)                                   Methanesulfinic acid, sodium salt (MW = 102.09) 24.23 g (237 mmol)                                              Methyl sulfoxide  170 ml                  ______________________________________                                    

Reagents were added to methyl sulfoxide and heated to 130° C. for 18hrs.The sodium methanesulfinate was partially insoluble at RT but went intosolution at 130° C. Sodium fluoride precipitated out of solution. Thereaction mixture was poured into 300 ml water. The product precipitatedout as a white solid. The reaction mixture was filtered. The productrecovered was washed with 100 ml water and 2×50 ml methanol to removemethyl sulfoxide. The solvent was evaporated from the product underreduced pressure affording 39.9 g of 2 as a white powder (86% isolatedyield). C¹³ -NMR (CDCl₃): 44.33, 128.25, 130.43, 139.70, 145.38, 190.72.

    ______________________________________                                        4-Methylsulfonylbenzaldehyde 2 from 4-Chlorobenzaldehyde                      ______________________________________                                         ##STR27##                                                                    ______________________________________                                          4-Chlorobenzaldehyde (MW = 140.57)                                                                      6.31 g (45 mmol)                                    Methanesulfinic acid, sodium salt (MW = 102.09) 7.5 g (74 mmol)                                          Methyl sulfoxide 50 ml                           ______________________________________                                    

Reagents were added to methyl sulfoxide and heated to 130° C. for 18hrs.

The sodium methanesulfinate was partially insoluble at RT but went intosolution at 130° C. Sodium chloride precipitated out of solution. Thereaction mixture was poured into 100 ml water. The product precipitatedout as a white solid. The reaction mixture was filtered. The productrecovered was washed with 50 ml water and 2×25 ml methanol to removemethyl sulfoxide. The solvent was evaporated from the product underreduced pressure affording 5.1 g of 4-methylsulfonyl benzaldehyde as awhite powder (62% isolated yield).

Horner/Wittig Route for the Preparation of1-(3-pyridyl)-2-(4-methylsulfonylphenyl)-ethane-1-one

    ______________________________________                                          #STR28##                                                                      #STR29##                                                                      Ref: H. Zimmer, J. P. Bercz, Liebigs Ann Chem. 1965, 686, 107-114.          ______________________________________                                                  Aniline            89.4 g (0.96 mol)                                  3-pyridinecarboxaldehyde 102.8 g (0.96 mol)                                   Ethanol 150 mL                                                                Diphenylphosphite 224.7 g (0.96 mol)                                        ______________________________________                                    

A solution of aniline in ethanol (50 mL) was added to a solution of3-pyridine carboxaldehyde in ethanol (100 mL) at 0° C. After 2 hoursdiphenylphosphite was added and stirring was continued at roomtemperature for 18 hours. Methyltertbutylether (400 mL) was added tofurther precipitate the product which was filtered, washed (MTBE) anddried under vacuum to afford 320 g (80%) of the Pyridylaminodiphenylphosphonate as a white solid. ¹³ -C NMR (CDCl3):

    ______________________________________                                          #STR30##                                                                     ##STR31##                                                                    ______________________________________                                            Pyridyl-amino diphenylphosphonate                                                                   14.0 g (0.034 mol)                                    10% KOH in MeOH 23 mL (0.04 mol)                                              Tetrahydrofuran 150 mL                                                        4-methanesulfonylbenzaldehyde 5.6 g (0.03 mol)                              ______________________________________                                    

10% KOH/MeOH (23 mL) was added over 10 minutes to a solution ofphosphonate (14.0 g) in tetrahydrofuran at -45° C. After a further 10minutes benzaldehyde was added in one portion and after 1 hour thereaction mixture was allowed to warm to ambient temperature. Aqueoushydrochloric acid (2N, 100 mL) was added and the solution was leftstanding for 18 hours. EtOAc (200 mL) and water (200 mL) were added andthe organic layer discarded. The acid layer wash basified (pH=9) withsodium carbonate and extracted with dichloromethane (2×150 mL). Theorganic layers were combined, dried (MgSO4) and concentrated.Trituration with hexanes afforded 4-methylsulfonyl benzyl-3-pyridylketone as a pale yellow solid (6.3 g; 76%). ¹³ -C NMR (D-6 DMSO): 196.4,153.6, 149.4, 140.8, 139.1, 135.7, 131.5, 130.9, 126.8, 123.9, 44.6 and43.5 ppm.

    ______________________________________                                          #STR32##                                                                      #STR33##                                                                       -                                                                             ##STR34##                                                                  ______________________________________                                                Aniline               4.47 g (0.05 mol)                                 3-pyridinecarboxaldehyde 102.8 g (0.05 mol)                                   Methanol 10 mL                                                                Diphenylphosphite 11.2 g (0.05 mol)                                           10% KOH in MeOH 28 mL (0.05 mol)                                              4-methanesulfonylbenzaldehyde 8.3 g (0.45 mol)                              ______________________________________                                    

A solution of aniline in methanol (5 mL) was added to a solution of3-pyridine carboxaldehyde in methanol (5 mL) at 0° C. After 2 hoursdiphenylphosphite was added and stirring was continued at roomtemperature for 18 hours. THF (100 mL) was added and the reaction wascooled to -40° C. 10% KOH/methanol (28 mL) was added and after 30minutes 4-methanesulfonylbenzaldehyde (8.3 g) was added. The reactionwas allowed to warm to room temperature and stirred for 18 hours. EtOAc(200 mL) and water (200 mL) were added and the organic layer discarded.The acid layer wash basified (pH=9) with sodium carbonate and extractedwith dichloromethane (2×150 mL). The organic layers were combined, dried(MgSO₄) and concentrated. Trituration with hexanes afforded4-methylsulfonyl benzyl-3-pyridyl ketone as a pale yellow solid (9.7 g;71%).

PREPARATION OF CHLOROMALONDIALDEHYDE

A number of routes are available for the preparation ofchloromalondialdehyde. ##STR35##

A detailed experimental is published in Houben-Weyl-Muller: Methoden derOrganischen Chemie, 4th Edit., Vol 7/1, Thieme Verlag, Stuttgart, 1954,page 119. The starting material 1,1,2,3,3-pentachloropropane iscommercially available from Pfaltz and Bauer.

    ______________________________________                                        Preparation from Mucochloric Acid                                             ______________________________________                                          #STR36##                                                                      #STR37##                                                                      The following is a slight variation of the original procedure of               Dieckmann (Ber. Deut. Chem. Ges. 1904, 37, 4638).                          ______________________________________                                                   Mucochloric acid   50.0 g (0.30 mol)                                 Aniline 54 mL (0.60 mol)                                                      Water 1000 mL                                                               ______________________________________                                    

To a solution of aniline in water at 85° C. in a vigorously stirred 2 Lflask was added mucochloric acid in small portions over 30 min. Onaddition of the mucochloric acid, a yellow color develops, which quicklydissipated. The reaction mixture stayed heterogeneous and filtration ofan aliquot after 30 min heating indicated completion of the reaction.

The reaction mixture was heated at 90° C. for 60 min., cooled to 50° C.and filtered. The filtercake was washed with 50 mL of 2N HCl and 100 mLof H₂ O. The product was dried in a N₂ stream to give 57 g (100% yield)of 3-anilido-2-chloro-acrolein as a gray solid. ¹³ C NMR (D₆ -DMSO inppm):108, 117, 124, 129, 140. 147, 182.

3-Anilido-2-chloro-acrolein 57 g (0.30 mol) 5N NaOH solution 120 mL (0.6mol)

A solution of 3-anilido-2-chloro-acrolein in 120 mL of 5N NaOH washeated to 100° C. for 90 min. The dark black solution was extractedtwice with 50 mL each of MTBE.

The first organic wash removed most of the dark color from the solution,and the second organic wash was only lightly colored.

On cooling the aqueous phase, a crystalline precipitate formed. Thisproduct was the 3-chloromalondialdehyde Na salt.

The aqueous phase was acidified by the addition of 60 mL of 37% HClsolution. The aqueous phase was extracted (MTBE/THF 50/50, 400 mL total)and the combined organic phases were dried over MgSO4. After treatmentwith Darco G60 and filtration through a plug of SiO2, the solution wasevaporated to give 19.6 g (62% overall yield) of chloromalondialdehydeas a dark solid. Recrystallization from ca. 10 mL of MTBE gave 11.13 gof pure chloromalondialdehyde as a tan solid. ¹³ C NMR (D₆ -DMSO inppm): 113, 175 (broad). ##STR38##

Arnold (Collect. Czech. Chem. Commun. 1961, 26, 3051) mentions theformation of 3-dimethylamino-2-chloro-acrolein by reaction ofchloroacetic acid with the Vilsmeyer reagent derived from POCl₃ and DMF.A variation and extension of his procedure prepareschloromalondialdehyde as its Na salt.

Oxalylchloride (280 mL, 3.2 mol) was added at 10° C. to 1000 mL of DMF.The reaction was highly exothermic and a heavy precipitate formed. Aftera 2 h age, chloroacetylchloride (110 mL, 1.4 mol) was added and thereaction mixture was warmed to 75° C. for 3 hours. Analysis of analiquot by ¹ H NMR indicated complete consumption of thechloroacetylchloride and the reaction mixture was quenched by additioninto 1 L of H₂ O. To the cooled solution was added 500 mL of a 50% NaOHsolution. The reaction mixture is heated to reflux for 5 hours. Oncooling a precipitate formed, which was filtered and washed with water.The tan solid was dried in a N₂ stream to give 84 g of a tan solid (54%yield). ##STR39##

A suspension of N,P-acetal (44.38 g, 97 wt %, 0.100 mol) andsulfonylbenzaldehyde (22.14 g, 94 wt %, 0.113 mol) in tetrahydrofuran(150 mL) and isopropyl alcohol (300 mL) at 25° C. was treated withpotassium tert-butoxide (71 mL, 1.6M in THF, 0.113 mol) over 2 hr. Theresulting solution was aged 30 min and was treated with 2 N hydrochloricacid (200 mL). The homogeneous reaction mixture was aged 1 h and washeated to 45° C. 5 N sodium hydroxide was added dropwise to the reactionmixture (71 mL). The reaction mixture is aged 1 h at 45° C. The reactionmixture is cooled to -15° C. over 3 h, and filtered. The cake is washedwith cold IPA/water (1:1, 2×150 mL), water (75 mL) and then dried invacuo to give 24.91 g (86% yield) of the ketosulfone as a off-whitesolid.

What is claimed is:
 1. A process for making compounds of Formula I##STR40## R¹ is selected from the group consisting of (a) CH₃,(b) NH₂,(c) NHC(O)CF₃, (d) NHCH₃ ;Ar is a mono-, di-, or trisubstituted phenylor pyridinyl (or the N-oxide thereof), Wherein the substituents arechosen from the group consisting of (a) hydrogen, (b) halo, (c) C₁₋₄alkoxy, (d) C₁₋₄ alkylthio, (e) CN, (f) C₁₋₄ alkyl, (g) C₁₋₄fluoroalkyl,R² is chosen from the group consisting of (a) F, Cl, Br, I(b) CN,the process comprising: condensing a compound of formula A1##STR41## under acidic conditions, and optionally in the presence of anon-reactive solvent and in the presence of an ammonium reagent, withcompound A2 ##STR42## to yield a compound of Formula I.
 2. A processaccording to claim 1 wherein the non-reactive solvent is acetic acid. 3.A process according to claim 1 wherein Ar is a mono- ordi-trisubstituted 3-pyridinyl.
 4. A process according to claim 1 whereinR¹ is CH₃ or NH₂.
 5. A process according to claim 1 wherein Ar is amono- or di-substituted 3-pyridinyl and the substituents are selectedfrom the group consisting of(a) hydrogen, (b) halo, (c) C₁₋₃ alkoxy, (d)C₁₋₃ alkylthio, (e) C₁₋₃ alkyl, (f) CF₃, and (g) CN.
 6. A processaccording to claim 1 wherein R¹ is CH₃ or NH₂ ; andAr is a mono- ordi-substituted 3-pyridinyl and the substituents are selected from thegroup consisting of(a) hydrogen, (b) halo, (c) C₁₋₃ alkyl, (d) CF₃, and(e) CN.
 7. A process according to claim 1 whereinR² is Cl; R¹ is CH₃ orNH₂ ; Ar is a mono-substituted 3-pyridinyl and the substituents areselected from the group consisting of hydrogen and C₁₋₃ alkyl.
 8. Aprocess for making compounds of Formula I useful in the treatment ofinflammation and other cyclooxygenase-2 mediated diseases ##STR43##wherein: R¹ is selected from the group consisting of(a) CH₃, (b) NH₂,(c) NHC(O)CF₃, (d) NHCH₃ ; Ar is a mono- di-, or trisubstituted phenylor pyridinyl (or the N-oxide thereof), wherein the substituents arechosen from the group consisting of(a) hydrogen, (b) halo, (c) C₁₋₄alkoxy, (d) C₁₋₄ alkylthio, (e) CN, (f) C₁₋₄ alkyl, (g) C₁₋₄fluoroalkyl,R² is chosen from the group consisting of (a) F, Cl, Br, I(b) CN,the process comprising: (a) reacting a compound of formula A2##STR44## in the presence of a second non-reactive solvent with a strongbase to yield the enolate of formula B1 ##STR45## wherein M ispotassium, lithium or sodium, and (b) reacting a compound of formula B1in the presence of a third non-reactive solvent with compound B2##STR46## wherein R³ is a leaving tosyl, mesyl or halo which afterheating in the presence of ammonia reagent, yields a compound of formulaI.
 9. A process according to claim 8 wherein Ar is a mono- ordi-substituted 3-pyridinyl.
 10. A process according to claim 8 whereinR¹ is CH₃ or NH₂.
 11. A process according to claim 1 wherein Ar is amono- or di-substituted 3-pyridinyl and the substituents are selectedfrom the group consisting of(a) hydrogen, (b) halo, (c) C₁₋₃ alkoxy, (d)C₁₋₃ alkylthio, (e) C₁₋₃ alkyl, (f) CF₃, and (g) CN.
 12. A processaccording to claim 8 wherein R¹ is CH₃ or NH₂ ; andAr is a mono- ordi-substituted 3-pyridinyl and the substituents are selected from thegroup consisting of(a) hydrogen, (b) halo, (c) C₁₋₃ alkyl, (d) CF₃, and(e) CN.
 13. A process according to claim 8 whereinR² is Cl; R¹ is CH₃ orNH₂ ; Ar is a mono-substituted 3-pyridinyl and the substituents areselected from the group consisting of hydrogen and C₁₋₃ alkyl.
 14. Aprocess according to claim 1 wherein R² is chloro.
 15. A processaccording to claim 8 wherein R³ is chloro.
 16. A process according toclaim 1 or 8 wherein the ammonium reagent is selected from ammonia andammonium acetate.
 17. A process according to claim 8 wherein the strongbase is lithium bis(trimethylsilyl)amide.
 18. A process according toclaim 8 wherein the third non-reactive solvent is toluene.
 19. Acompound according to claim 8 having the formula: ##STR47##